Irritable bowel syndrome (IBS) is the most common of all gastrointestinal disorders, affecting 10-20% of the general population and accounting for more than 50% of all patients with digestive complaints. However, studies suggest that only about 10% to 50% of those afflicted with IBS actually seek medical attention. Patients with IBS present with disparate symptoms such as, for example, abdominal pain predominantly related to defecation, diarrhea, constipation or alternating diarrhea and constipation, abdominal distention, gas, and excessive mucus in the stool. More than 40% of IBS patients have symptoms so severe that they have to take time off from work, curtail their social life, avoid sexual intercourse, cancel appointments, stop traveling, take medication, and even stay confined to their house for fear of embarrassment. The estimated health care cost of IBS in the United States is $8 billion per year (see, Talley et al., Gastroenterol., 109, 1736-1741 (1995)).
The precise pathophysiology of IBS is not well understood. Nevertheless, there is a heightened sensitivity to visceral pain perception, known as peripheral sensitization. This sensitization involves a reduction in the threshold and an increase in the gain of the transduction processes of primary afferent neurons, attributable to a variety of mediators including monoamines (e.g., catecholamines and indoleamines), substance P, and a variety of cytokines and prostanoids such as E-type prostaglandins (see, e.g., Mayer et al., Gastroenterol., 107:271-293 (1994)). Also implicated in the etiopathology of IBS is intestinal motor dysfunction, which leads to abnormal handling of intraluminal contents and/or gas (see, e.g., Kellow et al., Gastroenterol., 92:1885-1893 (1987); Levitt et al., Ann. Int. Med, 124:422-424 (1996)). Psychological factors may also contribute to IBS symptoms appearing in conjunction with, if not triggered by, disturbances including depression and anxiety (see, e.g., Drossman et al., Gastroenterol. Int., 8:47-90 (1995)).
The causes of IBS are not well understood. The walls of the intestines are lined with layers of muscle that contract and relax as they move food from the stomach through the intestinal tract to the rectum. Normally, these muscles contract and relax in a coordinated rhythm. In IBS patients, these contractions are typically stronger and last longer than normal. As a result, food is forced through the intestines more quickly in some cases causing gas, bloating, and diarrhea. In other cases, the opposite occurs: food passage slows and stools become hard and dry causing constipation.
Inflammatory bowel disease (IBD) is a heterogeneous group of diseases that have a common manifestation of (gut) mucosal inflammation. In general, IBD encompasses two major forms of intestinal inflammation: ulcerative colitis and Crohn's disease, which is also known also as Crohn's ileitis, regional enteritis, or granulomatous colitis. Estimates place the domestic prevalence of these conditions between one and two million patients, with similar rates in other northern European countries (see, Crohn's & Colitis Foundation of America 1/99 Update). The clinical and histopathologic features of IBD are well characterized; however, the etiology and pathogenesis of IBD are still subjects of intense research. Currently, a variety of medical treatment modalities are used, with moderate success, to both control active “flare-ups” of IBD as well as to maintain remission(s). Aminosalicylate preparations such as sulfasalazine and mesalamine are the most common anti-inflammatory agents which are used to control ulcerative colitis and, to a lesser extent, Crohn's disease. While the specific mechanism remains undefined, inhibition of eicosanoid mediators such as prostaglandins and thromboxanes is the probable mechanism of action (see, Stein et al., Gastroent. Clin. N Amer., 28:297-321 (1999)). Other typical treatments include corticosteroids and antibiotics such as metronidazole and ciprofloxacin for acute flares of disease. The other large category of drugs used in IBD is the immunomodulators, including azathioprine, methotrexate, and cyclosporine, the efficacy of which are principally related to their ability to inhibit T-cell related immune response and inflammatory cytokine cascades (see, Stotland et al., Primary Care, 23:577-608 (1996)). These treatments, unfortunately, induce worrisome side effects.
As mentioned, the causes of IBD remain obscure. A currently accepted hypothesis is that IBD represents an interaction between genetic and environmental factors, and implicates T-cell dysregulation, specifically an abnormally severe T-cell inflammatory response to mucosal antigens. Commensal gut flora is implicated as the source of such antigens. Regardless of the initial insult that activates the immune system, the inflammatory cascade which follows has been characterized. The Th cell cytokines IL-1 and TNF-α are considered to be central to the pathogenesis of IBD (see, Papadakis et al., Gastroent. Clin. N. Amer., 28:283-296 (1999)). Further down the inflammatory cascade are the eicosanoid products of arachidonic acid, particularly Prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4), which have been found in high levels in IBD patients (see, Stotland et al., supra).
Because the symptoms of IBS are similar or identical to the symptoms of so many other intestinal illnesses, it can take years before a correct diagnosis is made. For example, patients who have IBD, but who exhibit mild signs and symptoms such as bloating, diarrhea, constipation, and abdominal pain, may be difficult to distinguish from patients with IBS. As a result, the similarity in symptoms between IBS and IBD renders rapid and accurate diagnosis difficult. The difficulty in differentially diagnosing IBS and IBD hampers early and effective treatment of these diseases. Unfortunately, rapid and accurate diagnostic methods for definitively distinguishing IBS from other intestinal diseases or disorders presenting with similar symptoms are currently not available. The present invention satisfies this need and provides related advantages as well.